Results from Phase 3 KEYNOTE-966 to be presented at AACR 2023 Annual Meeting during Clinical Trials Plenary Session, included in official meeting press program and published simultaneously in The Lancet
RAHWAY, NJ, USA I April 16, 2023 I
Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced results from the Phase 3 KEYNOTE-966 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with standard of care chemotherapy (gemcitabine and cisplatin) for the first-line treatment of patients with advanced or unresectable biliary tract cancer (BTC). Results from the trial showed the KEYTRUDA regimen demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) compared to chemotherapy alone for these patients. These data are being presented during a Clinical Trials Plenary Session at the American Association for Cancer Research (AACR) 2023 Annual Meeting (abstract #CT008), were selected for the AACR press program and are being simultaneously published in
The Lancet
. The results are also being shared with regulatory authorities worldwide.
“Biliary tract cancer is rising in incidence worldwide, and unfortunately most patients are diagnosed with this devastating type of cancer at an advanced stage, when the five-year survival rate is less than 5%,” said Dr. Robin Kate Kelley, professor of clinical medicine in the division of hematology/oncology, University of California, San Francisco. “This trial shows that adding KEYTRUDA to chemotherapy holds the potential to extend life for these patients.”
After a median follow-up of 25.6 months (range, 18.3-38.4), KEYTRUDA plus chemotherapy reduced the risk of death by 17% (HR=0.83 [95% CI, 0.72-0.95]; p=0.0034) compared to chemotherapy alone for these patients. Median OS was 12.7 months (95% CI, 11.5-13.6) for the KEYTRUDA regimen versus 10.9 months (95% CI, 9.9-11.6) for chemotherapy alone. The one-year OS rate was 52% for the KEYTRUDA regimen versus 44% for chemotherapy alone; the two-year OS rates were 24.9% versus 18.1%, respectively. The OS results were generally consistent across subgroups.
The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 70% of patients receiving the KEYTRUDA regimen and 69% of patients receiving chemotherapy alone; TRAEs led to death in eight (2%) versus three (1%) patients, respectively. No new safety signals were identified. Grade 3-4 immune-mediated adverse events (AEs) occurred in 7% of patients receiving the KEYTRUDA regimen and 4% of patients receiving chemotherapy alone; immune-mediated AEs led to death in one patient (<1%) receiving the KEYTRUDA regimen.
“Based on these results, we hope to expand the use of KEYTRUDA in combination with chemotherapy as a first-line immunotherapy option for appropriate biliary tract cancer patients who may benefit and who are in need of new treatment options that may help them live longer,” said Dr. Scot Ebbinghaus, vice president, global clinical development, Merck Research Laboratories. “These results also demonstrate our commitment to improving outcomes for patients with different types of gastrointestinal cancers, including hepatobiliary tumors. We look forward to discussing these data with regulatory authorities.”
Merck has an extensive clinical development program evaluating KEYTRUDA as monotherapy and in combination across multiple gastrointestinal cancers including hepatobiliary, gastric, esophageal, pancreatic and colorectal cancers. In liver cancer, KEYTRUDA is being evaluated in earlier-stage hepatocellular carcinoma (HCC) in the KEYNOTE-937 study as well as in combination with LENVIMA
®
(lenvatinib, in collaboration with Eisai) and transarterial chemoembolization (TACE) in the LEAP-012 study.
This clinical development program for KEYTRUDA also includes KEYNOTE-811 in first-line advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, KEYNOTE-859 in HER2-negative gastric or gastroesophageal junction adenocarcinoma, and KEYNOTE-585 in early-stage gastric cancer. Additional exploration of KEYTRUDA is being conducted in combination with LENVIMA in advanced/metastatic esophageal cancer in the LEAP-014 study and gastric cancer in the LEAP-015 study. A coformulation of pembrolizumab and favezelimab (MK-4280A, Merck’s investigational anti-LAG-3 antibody) is being evaluated across multiple solid tumors, including colorectal cancer (MK-4280A-007,
NCT05064059
).
KEYNOTE-966 study design and additional data
KEYNOTE-966 is a randomized, double-blind Phase 3 trial (ClinicalTrials.gov,
NCT04003636
) evaluating KEYTRUDA in combination with gemcitabine and cisplatin compared to placebo plus gemcitabine and cisplatin for the first-line treatment of advanced and/or unresectable BTC. The primary endpoint was OS, and the secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety. The trial enrolled 1,069 patients who were randomized to receive KEYTRUDA (200 mg every three weeks for up to approximately two years) plus gemcitabine and cisplatin, or placebo plus gemcitabine and cisplatin.
Additional results from the trial showed the KEYTRUDA regimen prolonged DOR compared to chemotherapy alone. At the final analysis, median DOR was 8.3 months (range, 6.9-10.2) for the KEYTRUDA regimen and 6.8 months (range, 5.7-7.1) for chemotherapy alone. As of data cutoff for the first interim analysis (Dec. 15, 2021), which was specified as the final analysis for the secondary endpoints of PFS and ORR, the median study follow-up was 13.6 months. Median PFS was 6.5 months (95% CI, 5.7-6.9) for the KEYTRUDA regimen versus 5.6 months (95% CI, 5.1-6.6) for chemotherapy alone, with estimated 12-month PFS rates of 25% (95% CI, 21-30) versus 20% (95% CI, 16-24), respectively. The difference in PFS did not reach statistical significance. The ORR was 29% (95% CI, 25-33), with a complete response (CR) rate of 2% and a partial response rate of 27%, for patients receiving the KEYTRUDA regimen and 29% (95% CI, 25-33), with a CR rate of 1% and a PR rate of 27% for those receiving chemotherapy alone. The difference in ORR did not reach statistical significance. An exploratory analysis showed similar outcomes for PFS and ORR at the final analysis.
About biliary tract cancer (BTC)
Biliary tract cancer is a group of rare and highly aggressive cancers in the gallbladder and bile ducts. Biliary tract cancer is the second most common type of primary liver cancer after HCC, accounting for 15% of all liver cancers. It is estimated there are approximately 211,000 patients diagnosed with BTC and 174,000 patient deaths from the disease each year globally. Biliary tract cancer is most frequently diagnosed in patients between 50 to 70 years old, and 70% of BTC patients are diagnosed at an advanced stage. Patients diagnosed with BTC face a very poor prognosis, with a five-year survival rate of 2% for those with advanced disease, and across all stages of between 5% and 15%.
About KEYTRUDA
®
(pembrolizumab) injection, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.
Selected KEYTRUDA
®
(pembrolizumab) Indications in the U.S.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.
Non-Small Cell Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:
KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.
KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC.
Head and Neck Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.
KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.
Urothelial Carcinoma
KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):
KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
Microsatellite Instability-High or Mismatch Repair Deficient Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test.
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:
Cervical Cancer
KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).
KEYTRUDA, in combination with LENVIMA, is indicated for the first-line treatment of adult patients with advanced RCC.
KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
Endometrial Carcinoma
KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is pMMR as determined by an FDA-approved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
Tumor Mutational Burden-High Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.
Cutaneous Squamous Cell Carcinoma
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.
Triple-Negative Breast Cancer
KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Please see Prescribing Information for KEYTRUDA (pembrolizumab) at
http://www.merck.com.libproxy1.nus.edu.sg/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
and Medication Guide for KEYTRUDA at
http://www.merck.com.libproxy1.nus.edu.sg/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf
.
About LENVIMA
®
(lenvatinib); available as 10 mg and 4 mg capsules
LENVIMA, discovered and developed by Eisai, is a multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. In syngeneic mouse tumor models, the combination of lenvatinib with an anti-PD-1 monoclonal antibody decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity compared to either treatment alone.
LENVIMA
®
(lenvatinib) Indications in the U.S.
Please see Prescribing Information for LENVIMA (lenvatinib) at
http://www.lenvima.com/pdfs/prescribing-information.pdf
.
Merck’s focus on cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit
www.merck.com/clinicaltrials
.
About Merck
At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit
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SOURCE:
Merck
